rs28943591

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000414.4(HSD17B4):c.1471G>A(p.Ala491Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00495 in 1,585,784 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 23 hom. )

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 3.84

Variant links:

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012981385).

BP6

Variant 5-119515014-G-A is Benign according to our data. Variant chr5-119515014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119515014-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00355 (540/152178) while in subpopulation NFE AF= 0.00618 (420/67970). AF 95% confidence interval is 0.00569. There are 2 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4 linkuse as main transcript	c.1471G>A	p.Ala491Thr	missense_variant	17/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7 linkuse as main transcript	c.1471G>A	p.Ala491Thr	missense_variant	17/24	2	NM_000414.4	ENSP00000424940	P1	P51659-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00616

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00344

AC:

864

AN:

251252

Hom.:

AF XY:

0.00348

AC XY:

472

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00509

AC:

7303

AN:

1433606

Hom.:

Cov.:

AF XY:

0.00499

AC XY:

3566

AN XY:

715194

show subpopulations

Gnomad4 AFR exome

AF:

0.000912

Gnomad4 AMR exome

AF:

0.00521

Gnomad4 ASJ exome

AF:

0.000617

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.00620

Gnomad4 OTH exome

AF:

0.00410

GnomAD4 genome

AF:

0.00355

AC:

540

AN:

152178

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00618

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00556

Hom.:

Bravo

AF:

0.00418

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00311

AC:

378

Asia WGS

AF:

0.000289

AC:

AN:

3470

EpiCase

AF:

0.00780

EpiControl

AF:

0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HSD17B4: BP4, BS2 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2022	Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591). -

Bifunctional peroxisomal enzyme deficiency

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Perrault syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;T;.;.;.;T;.;T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

.;D;D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.028

MutationAssessor

Uncertain

2.6

M;.;M;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;N;.;.;N;.;.;.;N;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.098

T;T;.;.;T;.;.;.;T;T;.

Sift4G

Benign

0.24

T;T;.;.;T;.;.;.;T;T;.

Polyphen

0.62

P;.;P;.;.;.;P;.;.;P;.

Vest4

0.37

MVP

0.90

MPC

0.12

ClinPred

0.039

GERP RS

4.2

Varity_R

0.18

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over